P5378The methyltransferase SETD7 promotes myocardial ischemic injury by activating Hippo signalling
Notice bibliographique
Résumé
Abstract Introduction Despite significant advances in coronary revascularization, acute myocardial infarction remains the leading cause of heart failure and death worldwide. The Hippo pathway is a master regulator of cell survival during myocardial ischemia. Upon cellular stress, activation of Hippo signaling leads to cytosolic retention and degradation of the pro-survival transcription factor YAP. Post-translational modifications, namely methylation, critically affect protein functionality in conditions of cellular stress. The SET domain-containing lysine methyltransferase 7 (SETD7) - which induces a specific mono-methylation of both histone and non-histone proteins - has recently emerged as key player in the pathogenesis of vascular disease. However, the role of SETD7 in the heart is largely unknown. Purpose The present study investigates whether SETD7 regulates the Hippo pathway during myocardial ischemia. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to normal glucose levels or glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor [(R)-PFI-2] or its inactive enantiomer [(S)-PFI-2]. Western blot and real time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis was assessed by Caspase-3 activity assay. YAP localization was examined by confocal microscopy while its mono-methylation was assessed by immunoblotting. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates (male, 8–12 weeks old) underwent 1 h of left anterior descending (LAD) coronary artery ligation followed by 24 h of reperfusion. Infarct size was assessed by TTC staining and shown as infarct size per ventricle surface (I/V). Cardiac function was investigated at 24h by conventional and Tissue Doppler Imaging echocardiography (Vevo 3100, Visualsonics). Results GD for 15h in NRVMs led to both YAP phosphorylation and mono-methylation, and subsequent cytosolic retention, as assessed by confocal microscopy. Reduced nuclear content of YAP was confirmed by downregulation of YAP-dependent pro-survival genes, namely Ctgf and Fgf2. GD-induced YAP inactivation was associated with an increase in SETD7 expression. Interestingly, pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation, thus restoring nuclear retention of YAP and transcription of pro-survival genes in GD-treated NRVMs. Moreover, (R)-PFI-2 prevented NRVMs apoptosis. In line with our in vitro findings, SETD7−/− mice showed decreased infarct size as compared to WT littermates (I/V: 16.27%±2 vs. 20.54%±3, p<0.005, respectively). Consistently, cardiac function, as assessed by ejection fraction (EF: 46%±2 vs. 38%±5, p<0.001), fractional shortening (FS: 22%±1 vs. 18%±3, p<0.001) as well as by TDI, was preserved in mice lacking SETD7 as compared to WT animals. Conclusions Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a novel therapeutic approach to prevent myocardial ischemic damage.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».